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More Information on Apomorphine (Uprima)

Letter Urging Rejection of Apomorphine (Uprima)

June 5, 2000

Janet Woodcock, M.D.
Director, Center for Drug Evaluation and Research
Food and Drug Administration
5600 Fishers Lane
Rockville, MD 20857

Dear Dr. Woodcock:

We are writing to strongly urge the Food and Drug Administration (FDA) to reject the approval of Tap Holdings' (a joint venture with Abbott Labs) Uprima (apomorphine), a drug for the treatment of erectile dysfunction (ED). Despite the fact that this drug has been shown to be only marginally effective at the lower dose and to have significant, life-threatening toxicity at the higher dose, an FDA advisory committee voted 9 to 3, on April 10th of this year, that the risk-benefit ratio of the drug was acceptable. Our request is based on a review of several hundred pages of publicly available FDA documents that review the results of the clinical trials of this drug. If the FDA approves this drug, it is certain that it will have to be banned within a short time after marketing begins because of the high probability of further occurrence of the serious injuries it has already been found to cause.

The company has asked that three doses be marketed: 2 milligrams, 3 milligrams and 4 milligrams. The effectiveness of the low (2 mg) dose was so poor that in the long-term, flexible-dose studies, between 89% and 94% of men increased their dose to 4 mg, 5 mg, or 6 mg.[1] However, beginning at 4 mg, adverse events (AEs) dramatically increased, with incidence rates for nausea of approximately 20%, dizziness 14%, somnolence 11%, sweating 10%, vomiting 1-4%, hypotension 3-6%, and syncope (fainting) 1 to 2% (see Table.)

Syncope occurred in 34 men (1.4%) in Phase 2 and 3 trials at the 2 mg and 4 mg doses.[2]  The severity was such that several men required intravenous fluids, oxygen, and hospitalization.[3]  At the 4 mg dose, approximately 1 in 30 men had syncope or hypotension (with no cases in the placebo group).[4] These reported rates are undoubtedly lower than actually occurred since blood pressures were not systematically monitored during the clinical trials.

Because of syncope due to Uprima during clinical trials, one man lost consciousness when driving, resulting in an automobile accident. Another was injured in a fall: a 42-year-old man lost consciousness after a 5 mg dose of Uprima resulting in a skull fracture with a cortical contusion of the frontal lobe of the brain.[5] Concomitant use with nitrates and, possibly, drugs to lower blood pressure appears to pose another source of adverse reactions.[6]

Adverse events increased in frequency when patients took alcohol along with Uprima. The blood pressure of a 60-year-old man who drank 4 oz of vodka followed by 5 mg Uprima dropped to 55/38 and his electrocardiogram revealed new abnormalities consistent with decreased blood flow to the heart. His treatment included IV saline, oxygen, and 2 days hospitalization.[7] In general, use of Uprima with alcohol increased the incidence of dizziness, pallor, and hypotension by two- to three-fold. During the trials, men were instructed to limit yourself to a minimum amount of alcoholic beverages during the six hours prior to taking study drug.

Nausea was the most common adverse event (consistent with apomorphine's long-standing use to induce vomiting) and this was the most common reason for patients discontinuing the drug.[8] Patients were instructed to wait at least one hour after a full meal or eat some crackers ½ hour to one hour before taking Uprima if they hadn't eaten for several hours.

Mouth ulcerations or other oral pathology occurred in about 2% of patients, some of which took days to heal.[9] Local irritation was evidenced in mice, rats, and dogs as inflammation, hemorrhage, necrosis, and fibrosis at the injection sites.[10]

In the clinical trials, inclusion/exclusion criteria were very restrictive: Uprima was studied in a population of relatively healthy men with erectile dysfunction with no major organic etiology. All patients had to undergo nocturnal penile tumescence testing (NPT) at least 60 days prior to day one and demonstrate at least one successful erection. All men had to be judged in good general health as evidenced by medical history and physical examination ; all laboratory values had to be within 15% above or below normal range. Patients were excluded for neurologic disease, genitourinary disorders, hypogonadism, major psychiatric disorders, cardiovascular disease, gastrointestinal disease, any cancer (other than basal or squamous cell) that had not been in remission for at least 5 years, history of drug or alcohol abuse (within last 2 years), smoking more than 10 cigarettes/day (or equivalent use of other forms of tobacco), partners with major affective disorder, partners with history of female sexual dysfunction, or partners who were pregnant, lactating, or planning to become pregnant.

As  FDA's Medical Officer Dr. Hirsch repeatedly indicated, this is not indicative of the ED population at large. If it should be marketed, it will not be possible to restrict its use and one can expect a major increase in serious AEs. Dr. Mann remarked that in all other drugs approved for erectile dysfunction, these particular inclusion and exclusion criteria did not exist in the pivotal trials.[11]

The 5 mg and 6 mg doses were dropped from development because of the high incidence of adverse reactions; their importance lies in the increased incidence of serious adverse events coupled with highly variable serum blood levels such that  doses of 4 mg,  5 mg, and 6 mg may be indistinguishable in any given patient.[12]

The primary efficacy endpoint, as rated by the patient, was defined as the percentage of attempts resulting in an erection firm enough for intercourse. The most substantial clinical evidence came from three randomized, double-blind, placebo-controlled, two-period, cross-over studies that showed an average 12% increase in success over placebo at the 2 mg dose (34% vs. 46%) and an average increase of 20% at the 4 mg dose (34% vs. 54%).[13]

The agency is well aware that, particularly with the direct to consumer advertising and Internet sales, AEs are sure to occur with this sort of drug. Much of the prescribing will be for patients who do not meet the rigid clinical trial inclusion criteria and who, in many instances, will not follow the warnings about alcohol use. As discussed in the FDA review of the drug, The requirement that minimal alcohol be consumed prior to taking a tablet may not be practical to expect in a real-world situation.[14] In addition, those with cardiovascular disease will be at an especially increased risk for serious AEs.

In summary, the concerns of the advisory committee and the reviewing division included the following:

  1. The clinical trials did not look at a real-world population but at generally healthy men without an organic cause for ED who tested positive on nocturnal penile tumescence testing. 
  2. Although there was statistical significance in the improvement in erectile dysfunction, a robust clinical benefit was lacking, particularly at 2 mg. 
  3. The likelihood, based on the clinical trials, that 4 mg would likely be the actual clinical dose has serious implications because of the dramatically increased incidence in severe  adverse reactions with the higher doses. Overall, the choice is between a dose where the drug is safe (but not very effective), the 2 milligram dose, or effective (but not safe), the four milligram dose. 
  4. The likelihood that many patients would take alcohol at or around the time of their Uprima dose further increases the chance for serious AEs, of which hypotension and syncope are particularly worrisome. The actual incidence of hypotension is unknown since blood pressures were not systematically monitored during the trial. 
  5. For patients who are taking nitrates or drugs to lower blood pressure, there is an increased, but unknown, risk for hypotension; this situation has not been adequately studied. 
  6. It is not known what might happen to patients who combine Viagra with Uprima; the sponsor is studying this combination but has not yet provided any data. 
  7. Urgent medical intervention is often necessary to prevent serious injury (oxygen, IV fluids); what would patients do in such a situation at home and what would be the outcome if help were not forthcoming? 
  8. Past experience with black box warnings and other warnings  show that they do not prevent the need to eventually withdraw dangerous drugs from the market. 

We hope that the FDA will not make the mistake of being swayed by the company manufacturing this drug or the ill-considered vote by the advisory committee that the benefits of Uprima outweigh its risks. There have already been too many recently approved drugs which have had to be taken off the market after a sufficient number of quite predictable adverse reactions caused the deaths or serious injuries of patients using these drugs. Please overrule the dangerous advice of the advisory committee and refuse to approve Uprima. Otherwise, FDA will make another serious mistake, adding to the toll of people injured or killed by drugs which should never have been approved. We await a prompt response to this urgent request.

Sincerely,

Sidney M. Wolfe, M.D
Director

Elizabeth Barbehenn, Ph.D
Pharmacologist
Public Citizen's Health Research Group

Range of incidence of adverse events at the 2, 4, 5, and 6 mg doses* [15]

Adverse Event

Placebo 
(%)

Uprima

2mg #(%)

4 mg # (%)

5mg (%)

6mg (%)

Nausea

1-3

1.6-2.6

18-22

29-33

35-43

Dizziness

0-4

2.0-4.5

13-15

20

16-23

Somnolence

0-4

0.7-3.2

9-13

12

12-17

Sweating

0-1

0.7-2.6

9-10

15-17

20-21

Vomiting

0.0

0.0-1.3

1-4

7-10

9-13

Hypotension

0.0

0.0-1.2

3-6

2-7

4-5

Syncope

0.0

0.0-0.7

1-2

3-4

2

* frequency range in different trials         
#  dosages to be marketed


References

[1] Dr. Mark Hirsch, Advisory Committee for Uprima, April 10, 2000, p.105.

[2] FDA Medical Officer Summary for Uprima, p.67.

[3] Dr. Mark Hirsch, Advisory Committee for Uprima, pp.107-109.

[4] Advisory Committee for Uprima, p.107.

[5] FDA Medical Officer Summary for Uprima, p.59.

[6] Dr. Marianne Mann, Advisory Committee for Uprima, pp.120-121.

[7] Dr. Mark Hirsch, Medical Officer Summary for Uprima, p.61.

[8] FDA Medical Officer Summary for Uprima, p.56.

[9] Ibid; p.56.

[10] FDA Pharm/Tox Summary for Uprima, p.14

[11] Dr. Marianne Mann, Advisory Committee for Uprima, p.122.

[12] Dr. Mark Hirsch, Advisory Committee for Uprima, p.116.

[13] Ibid, p.103 (data are in a slide shown during the advisory committee meeting)

[14] FDA Medial Officer Summary for Uprima, p.124.

[15] Dr. Mark Hirsch, Advisory Committee for Uprima, compiled from several slides.

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